Alzheimer's: Pre-symptom biomarker changes could help early diagnosis

Evan Walker
Evan Walker TheMediTary.Com |
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A new study shows people had higher levels of an Alzheimer’s-associated protein in their spinal fluid years before their diagnosis. Tim E White/Getty Images
  • Alzheimer’s disease is the most common form of dementia, affecting around 40 million people worldwide.
  • Diagnosis is difficult and often delayed because all forms of dementia have similar symptoms.
  • Researchers believe that biomarkers in cerebrospinal fluid (CSF) and blood plasma may be a key to early diagnosis of Alzheimer’s disease.
  • Now, a long-term study from China has found marked differences in several biomarkers between people who went on to develop Alzheimer’s disease many years later and those who did not.

According to the Health Organization" rationale="Highly respected international organization">World Health Organization (WHO), some 55 million people worldwide have dementia, and the number is rising rapidly. A Lancet report estimates that by 2050, more than 150 million people will be living with dementia.

Between 60% and 80% of dementia cases are Alzheimer’s disease, which is characterized by a buildup of beta-amyloid and tau proteins in the brain.

Experts believe that these proteins, which form plaques and tangles, interfere with the functioning of nerve cells in the brain, leading to characteristic symptoms of memory loss and confusion.

Most existing treatments help manage the symptoms of Alzheimer’s disease but cannot halt the progress of the disease. However, for greatest benefit these treatments must be given early in the course of the disease so early diagnosis is key to slowing the progress of Alzheimer’s disease.

Recent research has focused on biomarkers in cerebrospinal fluid (CSF) and blood plasma as diagnostic indicators of Alzheimer’s disease.

Now, new research from China has mapped biomarkers over 20 years in a group of people who later did or did not develop Alzheimer’s disease. They found significant differences in the levels of beta-amyloid-42, tau, and other biomarkers over the course of the study.

The study is published in the New England Journal of Medicine.

Dr. Claire Sexton, Alzheimer’s Association senior director of scientific program and outreach, not involved in the current study, told Medical News Today:

“For a number of years, scientists have published proposals of what things may change when in the run-up to a diagnosis of Alzheimer’s dementia. This newly-published study is a notable addition for a number of reasons. By including assessments made over 20 years, the study was able to reveal changes up to 18 years prior to a diagnosis. Also, as this study comprised over 1,200 Chinese participants, it adds important representation of Asian populations to previous findings.”

This study formed part of the COAST study in China — a large-scale, wide-ranging study into many aspects of dementia.

The researchers enrolled participants ages 45–65 from January to June 2000. They excluded anyone with any cognitive impairment, a family history of Alzheimer’s disease, any life threatening disease, hearing or vision loss, or biomarker results at the start of the study.

They carried out follow-up tests every 2–3 years until 2020. These included examination of clinical records, CSF samples — by lumbar puncture — and blood samples, neuropsychological tests, and imaging tests.

At the final follow-up, the researchers matched 648 participants who had developed Alzheimer’s disease with the same number who had not developed Alzheimer’s disease, and compared the data from the two groups.

Dr. Emer MacSweeney, CEO and consultant neuroradiologist at Re:Cognition Health, not involved in this research, pointed out that the study, while having some valuable findings, also had limitations.

“The study’s clinical significance lies in advancing the understanding of Alzheimer’s disease by revealing the temporal dynamics of biomarker changes before clinical symptoms,” she told us. ”Key implications include the potential for early detection and accurate diagnosis, informing targeted therapeutic interventions, and considering APOE e4 genotype for personalised risk assessment.”

“However, limitations, such as a homogenous Han Chinese population and potential selection bias may affect the validity of making a generalization, of the finding, to other populations,” she added.

The researchers used enzyme-linked immunosorbent assay kits to test the levels of biomarkers in the CSF and blood samples. They also used magnetic resonance imaging (MRI) scans to assess any changes in brain volume over the course of the study.

The following biomarkers were measured:

  • beta-amyloid-42 — this is a major component of amyloid plaques in Alzheimer’s disease, and previous studies have found that it is decreased in CSF in people with Alzheimer’s disease
  • beta-amyloid-40 — low levels of this in CSF have previously been shown to be associated with Alzheimer’s disease
  • phosphorylated tau 181 — elevated levels of p-tau 181 in cognitively healthy individuals are associated with increased deposition of beta-amyloid
  • total tau concentrationhigher total tau levels are strongly associated with later development of Alzheimer’s disease.

The key finding of the study was that 18 years before Alzheimer’s disease diagnosis, levels of beta-amyloid-42 started to decrease, which they did not in people who were not diagnosed with Alzheimer’s disease. The ratio of beta-amyloid-42 and beta-amyloid-40 in the CSF diverged 14 years before diagnosis.

For tau protein, changes started 11 years before diagnosis, with phosphorylated tau 181 increasing in the Alzheimer’s disease group and total tau rising 10 years before diagnosis.

“The observed pattern in the rate of biomarker change, accelerating initially and then slowing down, may reflect the dynamic progression of pathological processes, potentially aligning with different stages of cognitive decline.”

– Dr. Emer MacSweeney, neuroradiologist

Dr. MacSweeney explained some of the other observed changes: “Higher NfL levels, detected 9 years before diagnosis, indicate neuroaxonal damage and axonal degeneration, reflecting neuronal injury associated with [Alzheimer’s disease],” she said.

“Reduction in hippocampal volume, starting 8 years before diagnosis, corresponds to structural , particularly in regions crucial for memory and learning, common in [Alzheimer’s disease].”

Dr. Emily Clark, DO, associate director of Alzheimer’s Disease Care, Research and Education Program (AD-CARE), at the University of Rochester Medical Center, not involved in the current study, told MNT that these changes were not surprising.

“The timing of the biomarker changes in this study is generally consistent with previously held knowledge on biomarker changes in Alzheimer’s disease. A temporal manner of biomarker changes in [Alzheimer’s disease] has been a hypothesis for many years that has been validated as biomarker testing advancements have been made in research settings,” she pointed out.

Dr. MacSweeney further explained, “These biomarker changes collectively provide insights into the underlying neuropathological events occurring during the preclinical stages of Alzheimer’s. The sequential nature of these changes suggests a temporal evolution of pathological processes, offering opportunities for early detection, intervention, and the development of targeted therapies.”

“However,” she added, “the precise interpretation of these biomarker alterations and their clinical implications may require further research and integration with other diagnostic and clinical measures.”

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